长链非编码RNA LINC01133对脑胶质瘤放射敏感性的影响及机制研究

Long non-coding RNAs (lncRNAs) have been confirmed to play critical regulatory roles in cancer biology. Although there is increasing evidence that lncRNAs play an important regulatory role in carcinogenesis and tumor progression, the underlying mechanism remains unknown. LINC01133 is a novel lncRNA associated with radioresistance of glioma by comparing different expression profiles between two glioma cell lines with different radiosensitivity using LncRNA microarray in our previous studies. We have identified that LINC01133 expression is associated with radioresistance and poor prognosis in glioma by expression analysis and the preliminary function research. In this study, we will explore the physiological and functional roles of LINC01133 in the radioresistance of glioma in vivo and in vitro through RNAi or gene over-expression cell model, and establishment of orthotopic implantation model of human glioma cells in nude mice. We will deeply detect the mechanism of LINC01133 in glioma radioresistance by using RNA pull-down, Mass spectrometry RNA immunoprecipitaiton and Chromatin Immunoprecipitation. The effect of LINC01133 and its related effectors will be identified by clinical multicenter sample of glioma. From this work, the functional role of LINC01133 in glioma radioresistance and its progression will be explored. Our study findings should provide new insight into the mechanism of metastasis of glioma and provide new targets for prognosis and preventing radioresistance of glioma.

长链非编码RNA(LncRNAs)是一类重要的细胞功能调控分子，研究显示LncRNAs参与肿瘤的发生、发展及治疗反应。LINC01133是我们前期应用lncRNA芯片从不同放射敏感性人恶性胶质瘤细胞系中筛选获得的与胶质瘤放射敏感相关的一种lncRNA；初步实验证实其与胶质瘤放射抵抗及预后不良密切相关。本课题通过体内外实验及脑胶质瘤原位移植动物模型探讨LINC01133在胶质瘤辐射抵抗中的生物学功能；并利用RNA pull down、质谱、RIP及CHIP等技术探讨其促进胶质瘤辐射抵抗的分子机制；再通过临床多中心大样本检测LINC01133及其相关蛋白在预警胶质瘤辐射抵抗及判断预后方面的作用。本项目将揭示LINC01133在胶质瘤辐射抵抗中的作用机制，对胶质瘤预后判断具有重要的理论及临床价值，从lncRNA这个新视野为阐明恶性胶质瘤放射抵抗的分子机制提供新依据与新思路。

长链非编码RNA（lncRNA）已成为各种生物过程中的重要调节分子。然而，lncRNA对胶质瘤细胞的放射敏感性的可能调控机制尚不清楚。本研究，我们研究了一种新的辐射相关lncRNA，LINC-RA1，对胶质瘤细胞的放射敏感性的影响及其相关机制。结果表明，LINC-RA1可增强体外和体内胶质瘤细胞放射抵抗性。当胶质瘤细胞暴露在电离照射下时，LINC-RA1可以结合组蛋白H2B，并调节H2B（H2Bub1）的泛素化，这是一种组蛋白修饰。H2bub1可以通过组蛋白驱逐、染色质松弛和随后获得修复蛋白来促进DNA双链断裂（DSB）的修复，其减少也可以激活自噬。我们的研究表明LINC-RA1可以促进胶质瘤细胞的放射抗性，可能成为影响胶质瘤的临床疗效的潜在靶点。